Cortical-basal ganglia circuits are involved in motor and reinforcement learning in many vertebrate species. Dysfunction of these circuits is thought to underlie a large number of human neurological and psychiatric diseases, including Parkinson's disease, in which motor learning and behavior are impaired coincident with loss of dopamine (DA) in the basal ganglia, and schizophrenia, in which fronto-striatal DA is dysregulated. The goal of this proposal is to test the hypothesis that DA in a songbird cortical-basal ganglia circuit is critical for vocal learning and performance. DA transmission will be reduced in a striatal nucleus, Area X, using molecular gene silencing to decrease expression of DA receptors in juvenile birds. Electrophysiological activity and vocalizations will be measured to examine the neuromodulatory effects of DA on neural activity in Area X during vocal practice (Specific Aim 1), and on song learning and stabilization (Specific Aim 2). Dopamine has also been hypothesized to be important for social context-dependent changes in song, which appears to switch from a 'flexible', perhaps learning-related state, to a more stable, 'performance' state in response to social cues. The effects of reduced DA transmission on neural activity and song production will therefore also be examined in behaviorally-relevant social contexts. The ability to perform molecular manipulations in a species in which neural activity can be correlated with a complex learned behavior has the potential to provide new mechanistic insights into basal ganglia function and disease. This project will contribute to NIMH's Priorities for Basic Brain and Behavioral Science Research, in that it develops molecular and genetic approaches for examining a complex neural circuit while the animal is rapidly developing a motor program in this circuit, and as the animal's motor behavior changes moment- by-moment in response to social context. In addition, because the basal ganglia circuit under study here is specialized for a discrete learned behavior, it may prove an especially tractable system for elucidating the signals present in such circuits in general. Changes in the basal ganglia are observed in many human neuropsychiatric diseases, but understanding of these is currently only at a very gross level. The goal of this project is to learn about the action of one particular neurotransmitter, dopamine, via its different receptors, at one particular place in the basal ganglia circuit. In addition to learning about how dopamine affects the behavioral output of this circuit, an increased understanding of the role of individual dopamine receptors may lead to refinement of dopamine drugs that are used to treat neuropsychiatric conditions. [unreadable] [unreadable] [unreadable]